: Brain or spinal cord trauma initiates an endogenous autodestructive process-a cascade of biochemical and metabolic changes that causes delayed neuronal cell death. Pharmacological treatment approaches have generally focused on inhibiting a single injury factor, despite the clear recognition that secondary tissue damage reflects a multifactorial injury process. The failure of any drug treatment strategy to date to improve recovery after human brain trauma supports the conclusion that targeting single components of secondary injury may not be sufficient to substantially modify posttraumatic recovery. The tripeptide, thyrotropin releasing hormone (TRH), modulates multiple components of the secondary injury cascade and treatment with TRH or certain TRH analogs improves outcome across a variety of neurotrauma models and species. In addition, TRH or related analogs have cognitive enhancing effects. However, these compounds also have other substantial physiological actions- including autonomic, endocrine and analeptic effects-that may not be optimal for treatment of severe head injury or for chronic administration (i.e. for cognitive action). For example, pressor effects may serve to increase intraparenchymal bleeding, increased body temperature may limit certain neuroprotective effects; and analeptic actions may compromise ability to utilize pharmacological coma treatments. Based upon extensive structure-activity studies, we have conceptualized and developed novel prototypic analogs of TRH and its dipeptide metabolite that exhibit both neuroprotective and nootropic properties, but appear to be devoid of other key physiological effects of TRH including endocrine, autonomic and analeptic actions. Moreover, using pharmacophore modeling techniques we have identified non-peptide mimics of the effective tripeptides. The proposed studies are intended to extend these preliminary observations by addressing the following hypotheses: (1) small peptide structures, related to TRH but devoid of the primary physiological actions of TRH, provide neuroprotection after traumatic brain injury, (2) neuroprotective actions of these compounds result from modulation of multiple components of the secondary injury cascade, including necrotic and apoptotic pathways; (3) these drugs may also be used to enhance long term cognitive function after brain injury; and (4) non-peptide mimics of these effector compounds may also serve as prototypes for novel drug discovery. Specific aims are to demonstrate that prototype tripeptide and dipeptide derivatives of TRH: (1) inhibit multiple components of the secondary injury cascade after traumatic brain injury; (2) have a high therapeutic index and a broad therapeutic window; (3) reduce both apoptotic and necrotic cell death; and 4) have nootropic properties and enhance cognitive function after chronic brain injury.